TW201213311A - Crystalline forms - Google Patents

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TW201213311A
TW201213311A TW100127719A TW100127719A TW201213311A TW 201213311 A TW201213311 A TW 201213311A TW 100127719 A TW100127719 A TW 100127719A TW 100127719 A TW100127719 A TW 100127719A TW 201213311 A TW201213311 A TW 201213311A
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cyclopropyl
fluorophenyl
heptanoic acid
dihydroxy
quinolin
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TW100127719A
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Chinese (zh)
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Der Schaaf Paul Adriaan Van
Fritz Blatter
Martin Szelagiewicz
Kai-Uwe Schoening
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Nissan Chemical Ind Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)

Abstract

The present invention is directed to new crystalline forms of Pitavastatin hemicalcium salt, referred to hereinafter as polymorphic Forms A, B, C, D, E and F, as well as the amorphous form. Furthermore, the present invention is directed to processes for the preparation of these crystalline forms and the amorphous form and pharmaceutical compositions comprising these crystalline forms or the amorphous form.

Description

201213311 六、發明說明： 【發明所屬之技術領域】 本發明針對匹伐他汀（？“2〃&^^111)鈣的新晶形和非晶 形，其製備方法，及含這些形式的藥學組成物。 本發明關於匹伐他汀鈣的新晶形和非晶形。亦已知匹 伐他汀的名稱爲NK-104、Itavastatin及Nisvastatin。已知 匹伐他汀鈣的化學名稱爲：（3Λ,5^)-7-[2-環丙基-4-(4-氟苯 基）喹啉-3-基]-3,5-二羥基-6-(5)-庚酸半鈣鹽。201213311 VI. Description of the Invention: [Technical Field] The present invention is directed to a novel crystalline form and amorphous form of pitavastatin (?"2" & ^^111) calcium, a preparation method thereof, and a pharmaceutical composition containing the same The present invention relates to the new crystalline form and amorphous form of pitavastatin calcium. It is also known that the names of pitavastatin are NK-104, Itavastatin and Nisvastatin. The chemical name of pitavastatin calcium is known as: (3Λ, 5^)- 7-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-(5)-heptanoic acid hemi-calcium salt.

【先前技術】 曰本Kowa股份有限公司近來已經開發出匹伐他汀鈣當 作一種新化學合成且有力的降血脂劑（statin)。根據所報導 的數據，匹伐他汀係劑量依賴性且似乎均等於Atorvastatin 。此新的降血脂劑在血膽固醇過高的病人之治療係安全的 且有良好耐受性的。與其它常用的藥物之交互作用可被視 爲極低的。 匹伐他汀的製備方法係敘述於EP-A-0304063和EP-A- 1099694中及在N. Miyachi等人於四面體通訊（1993)第34冊 第8267-8 270頁的刊物及K. Tak ah as hi等人於日本化學學會 201213311 通報（ 1 995)第68冊第2649-；2656頁的刊物中。這些刊物非常 詳細地說明匹伐他汀的合成，但是沒有說明匹伐他汀的半 鈣鹽。L. A. Sorbera等人在未來藥物（ 1 998)第23冊第847-8 5 9頁的刊物中及M. Suzuki等人在生物有機&醫藥化學通 訊（ 1 999)第9冊第2977-2982頁中敘述匹伐他汀鈣，然而未 提供其精確的製備程序。製備匹伐他汀鈣的完整合成程序 係敘述於EP-A-0520406中。在此專利所述的方法中，從水 溶液中沈澱出熔點1 90-1 92 t的白色結晶物質以獲得匹伐 他汀鈣。已知藥學物質可表現多晶形性。多晶形性常被定 義爲任何物質具有二或多種不同結晶構造的能力》當結晶 時，藥物亦可包封溶劑分子。這些溶劑化物或水合物係被 稱爲假多晶形。亦可能遭遇非晶形。不同的多晶形、假多 晶形或非晶形之相異處係在於它們的物理性質，如熔點、 溶解性等。這些會可觀地影響藥學性質，如溶解速率及生 物可利用性。亦經濟有利地爲產品可長時間安定的，而不 需要特殊的儲存條件。因此，評估藥物的多晶形性係重要 的。再者’藥物的新結晶多晶形式的發現係擴大材料的能 力範圍，使得配方科學家能用其設計出一種藥物的醫藥劑 型’具有目標的釋放輪廓或其它所欲的特性。我們現已驚 異地發現匹伐他汀鈣的新穎晶形，在本文中稱爲A、B、C 、D、E和F形式，以及匹伐他汀鈣的非晶形。 【發明內容】 因此’本發明係針對匹伐他汀鈣鹽（2 : 1)的多晶形A、 201213311 B、C、D、E和F以及非晶形。 本發明一目的係（3^,55)-7-(^2-環丙基_4_(4_氟苯基）喹 啉-3-基]-3,5-二羥基-6-(五）-庚酸半鈣鹽的結晶多晶形，在 此處稱爲形式A，其表現特徵X射線粉末繞射圖案，具有 以表1中之d-値（A)和2Θ所表示的特徵峰（vs =非常強的強度 ，s =強的強度’ m =中等強度，w =弱的強度，vw =非常弱的 強度）。 201213311 表1 :形式A的d-間隔及2Θ角 間隔[A] 角度[2Θ] 相對強度 17.6 5.0 S 13.0 6.8 S 9.7 9.1 S 8.8 10.0 W 8.4 10.5 m 8.1 11.0 m 6.7 13.3 vw 6.5 13.7 s 6.3 14.0 w 6.0 14.7 w 5.57 15.9 vw 5.25 16.9 w 5.17 17.1 vw 4.82 18.4 m 4.64 19.1 w 4.27 20.8 vs 4.20 21.1 m 4.10 21.6 m 3.87 22.9 m 3.74 23.7 m 3.67 24.2 s 3.53 25.2 w 3.29 27.1 m 3.02 29.6 vw 2.95 30.2 w 2.63 . 34.0 w 本發明另一目的係^心纟幻一-^-環丙基-^”-氟苯基 )喹啉-3-基]-3，5-二羥基-6-(五）-庚酸半鈣鹽的結晶多晶形， 在此處稱爲形式B，其表現特徵X射線粉末繞射圖案，具有 201213311 以表2中之d-値（A)和2Θ所表示的特徵峰。 表2 :形式Β的d-間隔及2Θ角 間隔[A] 角度[2Θ] 相對強度 19.0 4.6 W 16.6 5.3 VS 14.2 6.2 S 11.5 7.7 S 9.6 9.2 m 9.2 9.6 m 8.5 10.3 w 7.8 11.3 m 7.6 11.7 w 7.0 12.6 vw 6.8 13.0 w 6.4 13.9 m 6.0 14.7 vw 5.94 14.9 w 5.66 15.6 w 5.43 16.3 m 5.22 17.0 vw 5.10 17.4 vw 4.92 18.0 w 4.74 18.7 m 4.59 19.3 m 4.43 20.0 s 4.33 20.5 w 4.26 20.8 m 4.19 21.2 W，肩部 4.13 21.5 m 3.97 22.4 m 3.83 23.2 s 3.73 23.8 m 3.64 24.4 vw 3.53 25.2 W，寬 3.42 26.0 w 3.37 26.4 vw 3.30 27.0 w 3.19 27.9 vw 3.09 28.9 w 201213311 本發明又一目的係（3Λ，55)-7-[2-環丙基-4-(4-氟苯基 )唾啉-3 -基]-3，5 -二羥基-6 - (£)-庚酸半鈣鹽的結晶多晶形， 在此處稱爲形式C，其表現特徵X射線粉末繞射圖案，具有 以表3中之d-値（A)和2Θ所表示的特徵峰。 表3 :形式C的d-間隔及2Θ角 間隔[Al 角度『2Θ1 相對強度 21.6 4.1 m 15.9 5.6 S 11.4 7.8 m 10.6 8.3 m 8.6 10.3 m 7.7 11.6 w 5.06 17.5 w 4.95 17.9 w 4.74 18.7 m 4.55 19.5 s 4.31 20.6 m 4.13 21.5 vw 4.06 21.9 m 3.84 23.1 m 3.71 24.0 w 3.58 24.8 w 本發明再一目的係（3/?，5 5)-742-環丙基_4_(4_氟苯基） 嗤咐-3-基]-3,5-二羥基_6_(五）_庚酸半鈣鹽的結晶多晶形， 在此處稱爲形式D ’其表現特徵X射線粉末繞射圖案，具 有以表4中之d-値（A)和所表示的特徵峰。 -10- 201213311 表4 :形式D的d-間隔} 間隔[A] 1 _ 角度[2Θ] 相對強度Ί 17.5 _ 5.0 ^— m 13.5 _ 6.5 m 13.0 _ 6.8 -----^^ S 10.1 _ 8.7 m 8.8 _ 10.0 —— m 8.6 10.2 m 8.2 10.8 --—--- m 6.8 13.1 w 6.55 13.5 m 6.20 ... 14.3 s 5.78 15.3 vw 5.52 16.1 m 5.28 16.8 w 4.87 18.2 w 4.80 18.5 -------— m 4.66 19.0 w 4.46 19.9 m 4.34 20.5 ---— m 4.23 21.0 vs 4.09 21.7 s 3.99 22.3 w 3.80 23.4 m 3.70 24.0 m 3.47 25.6 — w 3.40 26.2 m 本發明又一目的係（3Α，5·5)-7-[2-環丙基 ' (4 ·氟苯 喹琳_3·基]-3,5-二羥基_6_(五）_庚酸半鈣鹽的 J本口日日多晶Λ[Prior Art] Ko本Kowa Co., Ltd. has recently developed pitavastatin calcium as a new chemically synthesized and potent statin. Based on the data reported, pitavastatin was dose-dependent and appeared to be equal to Atorvastatin. This new hypolipidemic agent is safe and well tolerated in the treatment of patients with high blood cholesterol. Interaction with other commonly used drugs can be considered extremely low. The preparation of pitavastatin is described in EP-A-0304063 and EP-A-1099694 and in the publication of N. Miyachi et al. in Tetrahedron Communication (1993), Vol. 34, No. 8267-8 270, and K. Tak. Ah ah as et al., in the publication of the Japanese Chemical Society 201213311 (1 995), vol. 68, pp. 2649-; 2656. These publications describe in great detail the synthesis of pitavastatin, but do not specify the hemi-calcium salt of pitavastatin. LA Sorbera et al., in the publication of Future Medicines (1 998), Volume 23, 847-8 5 9 and M. Suzuki et al., Bioorganic & Pharmaceutical Pharmacy Newsletter (1 999), Vol. 9, No. 2977-2982 The pitavastatin calcium is described, but its precise preparation procedure is not provided. A complete synthetic procedure for the preparation of pitavastatin calcium is described in EP-A-0520406. In the process described in this patent, a white crystalline material having a melting point of 1 90-1 92 t is precipitated from an aqueous solution to obtain pitavastatin calcium. Pharmaceutical substances are known to exhibit polymorphism. Polymorphism is often defined as the ability of any material to have two or more different crystal structures. When crystallized, the drug can also encapsulate solvent molecules. These solvates or hydrates are referred to as pseudopolymorphs. It may also be amorphous. Different polymorphs, pseudopolymorphs or amorphous phases differ in their physical properties such as melting point, solubility and the like. These can significantly affect pharmaceutical properties such as dissolution rate and bioavailability. It is also economically advantageous for the product to be stable for long periods of time without the need for special storage conditions. Therefore, it is important to evaluate the polymorphism of a drug. Furthermore, the discovery of the new crystalline polymorphic form of the drug broadens the range of capabilities of the material, allowing formulators to design a pharmaceutical dosage form with a targeted release profile or other desired property. We have now surprisingly discovered the novel crystalline form of pitavastatin calcium, referred to herein as Forms A, B, C, D, E, and F, and the amorphous form of pitavastatin calcium. SUMMARY OF THE INVENTION Accordingly, the present invention is directed to polymorph A of the pravastatin calcium salt (2:1), 201213311 B, C, D, E, and F, and amorphous. One object of the present invention is (3^,55)-7-(^2-cyclopropyl-4(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-(f) a crystalline polymorph of heptanoic acid hemi-calcium salt, referred to herein as Form A, which exhibits a characteristic X-ray powder diffraction pattern having characteristic peaks represented by d-値(A) and 2Θ in Table 1 (vs = very strong strength, s = strong strength 'm = medium strength, w = weak intensity, vw = very weak intensity) 201213311 Table 1: d-interval and 2 间隔 angular spacing of form A [A] angle [ 2Θ] Relative strength 17.6 5.0 S 13.0 6.8 S 9.7 9.1 S 8.8 10.0 W 8.4 10.5 m 8.1 11.0 m 6.7 13.3 vw 6.5 13.7 s 6.3 14.0 w 6.0 14.7 w 5.57 15.9 vw 5.25 16.9 w 5.17 17.1 vw 4.82 18.4 m 4.64 19.1 w 4.27 20.8 vs 4.20 21.1 m 4.10 21.6 m 3.87 22.9 m 3.74 23.7 m 3.67 24.2 s 3.53 25.2 w 3.29 27.1 m 3.02 29.6 vw 2.95 30.2 w 2.63 . 34.0 w Another object of the invention is 纟 纟 - -^-cyclopropyl Crystalline polymorph of -^"-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-(penta)-heptanoic acid hemi-calcium salt, referred to herein as Form B, exhibiting characteristics X-ray powder diffraction pattern , with 201213311 characteristic peaks represented by d-値(A) and 2Θ in Table 2. Table 2: d-spacing and 2Θ angular spacing of the form Β [A] Angle [2Θ] Relative intensity 19.0 4.6 W 16.6 5.3 VS 14.2 6.2 S 11.5 7.7 S 9.6 9.2 m 9.2 9.6 m 8.5 10.3 w 7.8 11.3 m 7.6 11.7 w 7.0 12.6 vw 6.8 13.0 w 6.4 13.9 m 6.0 14.7 vw 5.94 14.9 w 5.66 15.6 w 5.43 16.3 m 5.22 17.0 vw 5.10 17.4 vw 4.92 18.0 w 4.74 18.7 m 4.59 19.3 m 4.43 20.0 s 4.33 20.5 w 4.26 20.8 m 4.19 21.2 W, shoulder 4.13 21.5 m 3.97 22.4 m 3.83 23.2 s 3.73 23.8 m 3.64 24.4 vw 3.53 25.2 W, width 3.42 26.0 w 3.37 26.4 vw 3.30 27.0 w 3.19 27.9 vw 3.09 28.9 w 201213311 A further object of the invention is (3Λ,55)-7-[2-cyclopropyl-4-(4-fluorophenyl)sallin-3-yl]-3,5- The crystalline polymorph of dihydroxy-6-(£)-heptanoic acid hemi-calcium salt, referred to herein as Form C, exhibits a characteristic X-ray powder diffraction pattern having d-値(A) in Table 3 and The characteristic peak represented by 2Θ. Table 3: d-space and 2 corner spacing of Form C [Al angle "2Θ1 Relative intensity 21.6 4.1 m 15.9 5.6 S 11.4 7.8 m 10.6 8.3 m 8.6 10.3 m 7.7 11.6 w 5.06 17.5 w 4.95 17.9 w 4.74 18.7 m 4.55 19.5 s 4.31 20.6 m 4.13 21.5 vw 4.06 21.9 m 3.84 23.1 m 3.71 24.0 w 3.58 24.8 w A further object of the invention is (3/?, 5 5)-742-cyclopropyl_4_(4-fluorophenyl) 嗤咐- a crystalline polymorph of 3-yl]-3,5-dihydroxy-6-(penta)-heptanoic acid hemi-calcium salt, referred to herein as Form D' which exhibits a characteristic X-ray powder diffraction pattern, having D-値(A) and the characteristic peaks indicated. -10- 201213311 Table 4: d-spacing of form D} Interval [A] 1 _ Angle [2Θ] Relative strength Ί 17.5 _ 5.0 ^— m 13.5 _ 6.5 m 13.0 _ 6.8 -----^^ S 10.1 _ 8.7 m 8.8 _ 10.0 —— m 8.6 10.2 m 8.2 10.8 ------ m 6.8 13.1 w 6.55 13.5 m 6.20 ... 14.3 s 5.78 15.3 vw 5.52 16.1 m 5.28 16.8 w 4.87 18.2 w 4.80 18.5 ---- --- m 4.66 19.0 w 4.46 19.9 m 4.34 20.5 --- m m 4.23 21.0 vs 4.09 21.7 s 3.99 22.3 w 3.80 23.4 m 3.70 24.0 m 3.47 25.6 — w 3.40 26.2 m Another object of the invention (3Α, 5 ·5) 7-[2-cyclopropyl' (4 · fluorobenzoquine _3 · yl]-3,5-dihydroxy _6_(f)-heptanoic acid hemi-calcium salt Crystal

在此處稱爲形式Ε，其表現特徵X射線粉末繞射圖案，J 以表5中之d·値（Α)和2θ所表示的特徵峰。 -11 - 201213311 表5 :形式E的d-間隔及2Θ角It is referred to herein as a form Ε which exhibits a characteristic X-ray powder diffraction pattern, and J has characteristic peaks represented by d·値(Α) and 2θ in Table 5. -11 - 201213311 Table 5: d-space and 2 corners of Form E

間隔[Α] 角度[2Θ] 相對強度 20.0 4.4 VW 17.7 5.0 S 13.4 6.6 S 13.1 6.8 S 10.0 8.9 S 8.8 10.0 m 8.6 10.3 S 8.2 10.8 m 6.6 13.3 s 6.5 13.6 τη 6.3 14.0 s 5.84 15.2 VW 5.56 15.9 w 5.39 16.4 w 5.24 16.9 VW 4.99 17.8 VW 4.84 18.3 m 4.69 18.9 w 4.39 20.2 vs 4.34 20.4 m 4.30 20.7 m 4.24 20.9 m 4.21 21.1 vs 4.12 21.6 m 4.08 21.7 m 3.99 22.3 m 3.77 23.5 m 3.73 23.8 m 3.69 24.1 w 3.60 24.7 VW 3.50 25.4 VW 3.35 26.6 m 2.96 30.2 w 2.64 34.0 VW -12- 201213311 本發明猶一目的係（3^?，5 5)-7-[2-環丙基-4-(4-氟苯基） 喹啉-3-基]-3,5-二羥基-6-(五）-庚酸半鈣鹽的結晶多晶形， 在此處稱爲形式F，其表現特徵X射線粉末繞射圖案，具有 以表6中之d-値（A)和2 Θ所表示的特徵峰。 -13- 201213311 6 =形式F的d-間隔及2Θ角 間隔[A] 角度[2Θ] 相對強度 17.2 5.1 m 15.8 5.6 W 12.6 7.0 S 10.0 8.8 m 9.2 9.6 s 8.7 10.2 w 8.1 10.9 m 7.8 11.3 w 7.4 11.9 m 7.1 12.5 m 6.8 13.0 s 6.5 13.7 m 6.2 14.4 s 6.04 14.7 m 5.79 15.3 vw 5.70 15.5 w 5.28 16.8 m 5.03 17.6 w 4.85 18.3 m 4.61 19.3 m 4.51 19.7 m 4.30 20.6 m 4.18 21.2 vs 4.08 21.8 s 3.90 22.8 s 3.84 23.1 w 3.74 23.8 W，肩部 3.69 24.1 s 3.59 24.8 s 3.46 25.7 m 3.40 26.2 vw 3.35 26.6 m 3.31 26.9 w 3.14 28.4 w 3.02 29.5 w 3.00 29.8 vw 2.89 30.9 m -14- 201213311 實驗細節的小變化可能造成χ射線粉末繞射圖案中的 特徵峰之d-値（A)和2Θ的小偏差》 本發明另一目的係（3Λ，5·5)-7-[2-環丙基-4-(4-氟苯基） 唾啉-3-基]-3,5-二羥基-6-(£：)-庚酸半鈣鹽的非晶形，其表 現第7圖中所示的特徵X射線粉末繞射圖案。 粉末X射線繞射係在使用Cu k(a 1)輻射（ 1.54060A)的 Philips 1710粉末繞射計上進行；2Θ角係以±0.1-0.2°的實驗 誤差作記錄。X射線粉末繞射圖案的討論可見於紐約J. Wiley出版社 Η. P· Klug及 L. E. Alexander的「X射線繞射 程序」中。 再者，本發明係針對匹伐他汀齡的形式A、B、C、D 、E和F以及非晶形之製備方法。 一般可由匹伐他汀鈉與〇&(：丨2在水性反應介質中反應 而製備形式Α»或者，亦可在現場由自由酸（（3i?，5S)-7-[2-環丙基-4-(4-氟苯基）喹啉-3-基]-3,5-二羥基- 6-(E)-庚酸）或 對應的內醋與Ca(〇H)2反應而獲得本發明的形式a。水性反 應介質通常含有至少80重量％的水；較佳爲其係 水或含少量來自前步驟的溶劑及/或反應物的水。形式A 可含有最局1 5 %水，較佳約3至1 2 °/〇，更佳9至1 1 %水。 形式B通常可藉由將形式A懸浮在含水當作共溶劑的乙 醇中而製得。 形式C通常可藉由將形式a懸浮在含水當作共溶劑的異 丙醇中而製得。水量較佳爲約1至5 0 %，尤其1至2 0 %，且 更佳約5%。形式C亦可由異丙醇與酮溶劑的混合物來製得 -15- 201213311 。較宜地，酮溶劑係丙酮，而酮溶劑的量係約1至3 0%，更 佳約1 0 %。水量較佳爲約1至2 0 %，更佳約5 %。 形式D通常可藉由將形式A懸浮在無水乙醇中而製得 〇 形式E通常可藉由將形式A懸浮在含水當作共溶劑的 1，4 -二噁烷中而製得。水量較佳爲約1至5 0 %。 形式F通常可藉由將形式A懸浮在含水當作共溶劑的甲 醇中而製得β水量較佳爲約1至50%。 在上述方法中，可將少量所欲之晶形的種晶加到反應 混合物中。較宜地，該少量係約1至2 0重量％，較佳約5重 量％。可在閒始結晶的步驟（例如冷卻、添加非溶劑等，如 上述）之前或之後，添加種晶。在開始結晶之前的添加係 屬於技術上特別感趣的。 .通常可將非溶劑加到匹伐他汀鈣在有機溶劑中的濃縮 溶液以製備非晶形。非溶劑例如可爲庚炕或甲基第三丁基 醚，而有機溶劑的例子爲1,4-二噁烷、四氫呋喃及乙基甲 基酮。較佳爲非溶劑與溶劑係不可互溶的。亦可藉由匹伐 他汀鈣水溶液的冷凍乾燥來製備非晶形》 多晶形A、Β、C、D、Ε、F以及非晶形的製備通常係 在實質上純的反應系統中進行，該系統主要由特定的離析 物（較佳爲實質晶形）及上述的溶劑及/或非溶劑所構成。 本發明另一目的爲本質上無殘留有機溶劑的匹伐他汀 鈣之晶形的製備方法。 特別地，本發明關於本質上無殘留有機溶劑的匹伐他 -16- 201213311 汀錦之晶形的製備方法，其係藉由使匹伐他汀鈣的晶形暴 露於具有所界定的相對空氣濕度之大氣中。 更特別地，本發明係針對本質上無殘留有機溶劑的匹 伐他汀鈣之任何晶形或非晶形的製備方法。這些例如可藉 由使晶形或非晶形暴露於具有相對空氣濕度爲5至1 〇〇%的 大氣中而製得。較宜地’這些係藉由暴露於具有所界定的 相對空氣濕度之惰性氣流中，以使水交換殘留的有機溶劑 而製得。通常，使用5至100%的相對空氣濕度，尤其4〇至 8 0%。 本發明另一目的爲藥學組成物，其包含有效量的匹伐 他汀鈣之結晶多晶形A、B、C、D、E或F或非晶形，及藥 學上可接受性載體。 這些多晶形可用當作單一成分或當作與其它晶形或非 晶形的混合物。 就匹伐他汀鈣的新穎多晶形和非晶形而官，較佳爲這 些含有25-1 00重量％的至少一種該新穎形式，尤其5〇_1〇〇 重量％，此係以匹伐他汀鈣的總量爲基準。較宜地，匹伐 他汀鈣的新穎多晶形或非晶形之量係7 5 -1 0 〇重量％，尤其 90-1 00重量％。高度較宜的是95- 1 00重量％。 本發明的組成物包筠含有至少一種新穎形式的粉末、 顆粒.、凝聚物及其它固體組成物。此外，本發明所考慮的 組成物可更包括稀釋劑，如衍生自纖維素的材料，如粉狀 纖維素、微晶纖維素、微細纖維素、甲基纖維素、乙基纖 維素、經乙基纖維素、羥丙基纖維素、羥丙基甲基纖維、 -17- 201213311 羧甲基、纖維素鹽及其它經取代和未經取代的纖維素；澱 粉；預膠凝澱粉：無機稀釋劑，如碳酸鈣及二磷酸鈣及其 它製藥工業所已知的稀釋劑。其它適合的稀釋劑包括蠟、 糖及糖醇如甘露糖醇及山梨糖醇、丙烯酸醋聚合物及共聚 物，以及果膠、糊精及明膠。 在本發明所考慮範圍內的其它賦形劑包括黏合劑，如 阿拉伯膠、預膠凝澱粉、藻酸鈉、蔔萄糖及其它在濕和乾 顆粒化或直接壓錠程序所用的黏合劑》亦可存在於固體組 成物中的賦形劑係包括崩散劑如澱粉甘醇酸鈉、聚乙烯聚 吡咯啶酮、低取代的羥丙基纖維素等等。此外，賦形劑亦 可包含製錠潤滑劑如硬脂酸鎂和鈣以及硬脂基富馬酸鈉； 調味劑：甜味劑；防腐劑；藥學上可接受性染料及助流劑 如二氧化矽。 劑量包括適合於口服、頰含、直腸、非經腸胃（包括 皮下、肌內及靜脈內）、吸入及眼用給藥的劑量。雖然在 特定的案例中最適合的途徑係取決於所要治療的症狀之性 質和嚴重性，但本發明的最佳途徑係口服。劑量可方便地 存在於單位劑型中且可藉由藥學技藝中所週知的任何方法 來準備。 劑型包括固體劑型，如錠片、粉末、膠襄、栓劑、香 囊、糖錠及鬆渣以及液體懸浮液和酏劑。所說明非意欲用 於限制，而且本發明亦非意欲屬於匹伐他汀鈣的真溶液而 喪失匹伐他汀鈣的固體形式。然而，使用新穎形式來製備 該溶液係爲視爲在本發明所考慮的範圍內。 -18- 201213311 當然，膠囊型劑將含有在膠囊內的固體組成物，該膠 囊可由明膠或其它習用的包封材料所製得。錠片及粉末可 經被覆。錠片及粉末可被腸衣所被覆。經腸衣被覆粉末可 具有被覆層，此被覆層包含苯二甲酸及醋酸纖維素、羥丙 基甲基_纖維素苯二甲酸醋、聚乙烯醇苯二甲酸酯、羧甲 基乙基纖維素、苯乙烯與馬來酸的共聚物 '甲基丙烯酸與 甲基丙烯酸甲酯的共聚物，及類似的物料，且若須要，它 們亦可用適合的塑化劑及/或增量劑。經被覆的錠片可在 錠片的表面上具有被覆層，或可爲一種錠片，其包含粉末 及具有腸衣的顆粒。 本發明之藥學組成物的較佳單位劑量典型上係含有 0.5至100毫克的新穎匹伐他汀鈣形式及其與其它者的混合 物，或匹伐他汀鈣的其它形式。更通常地，匹伐他汀鈣的 合計重量係形成2.5毫克至8 0毫克的單位劑量，例如5、1 0 、20或40毫克。 【實施方式】 以下實施例更詳細說明本發明。溫度和爲攝氏度。 實施例1 :形式A的製備 使4.15克（3^?，55)-7-[2-環丙基-4-(4-氟苯基）喹啉-3-基 ]-3,5 ·二羥基-6-(五）-庚酸第三丁基醋（匹伐他汀第三丁基酯） 懸浮於甲基第三丁基醚和甲醇（1〇: 3)的52毫升混合物中。 於此混合物內，加入2.17毫升4MNaOH水溶液，於50。C將 -19- 201213311 所產生的微黃色溶液攪拌2.5小時。將反應混合物冷卻至 室溫，接著添加50毫升水及攪拌另一小時。水相分離及被 20毫升甲基第三丁基醚莘取一次》於此水溶液中，在1小 時內加入0.58克CaCl2在80毫升水中的溶液。於室溫攪拌 所得到的懸浮液約1 6小時。將懸浮液過濾及在40 °C和5 0 mbar乾燥所得到的固體歷約1 6小時。所得到的產物爲晶形 A，其經X射線粉末繞射圖案所鑑定，如第1圖所示。藉由 熱重量分析法聯合FT-IR光譜法來更進一步鑑定所獲得的 形式A，透露約10%的水含量，而微差掃描量熱法透露95°C 的熔點。 實施例2 :形式B的製備 使100毫克匹伐他汀鈣形式A懸浮於2毫升水中及於室 溫攪拌30分鐘’接著添加2毫升乙醇及另攪拌18小時。將 懸浮液過濾及在空氣中乾燥，產生36毫克形式B。藉由X射 線粉末繞射圖案來鑑定所得到的晶形B，如第2圖所示。藉 由熱重量分析法聯合FT-IR光譜法來更進—步鑑定所獲得 的形式B，透露約1 0 %的水含量。 實施例3 :形式C的製備 使62毫克匹伐他汀鈣形式A懸浮於含5%水的2毫升異 丙醇中。將此懸浮液加熱到60 °C，同時讓形式a幾乎完$： 溶解，及再度冷卻到室溫。在此溫度攪拌懸浮液66小時》 過爐所得到的懸浮液，用一些含5 %水的異丙醇來洗—次， •20- 201213311 及在空氣中乾燥。藉由χ射線粉末繞射圖案來鑑定所得到 的晶形C，如第3圖所示。藉由熱重量分析法聯合FT-IR光 譜法來更進一步鑑定所獲得的形式c’透露樣品含有約 6.3 %異丙醇及少量的水。 實施例4 :形式C的製備 使65毫克匹伐他汀鈣形式A懸浮於0.9毫升異丙醇、 0.1毫升丙酮及40微升水的混合物中。攪拌此懸浮液約1小 時以讓其幾乎完全溶解。用4毫克形式C(來自實施例3)來 播種，及攪拌2小時以形成濃縮的懸浮液。用等量的如上 述之溶劑混合物來稀釋此懸浮液，及攪拌另40小時。將懸 浮液過濾，及在40°C乾燥所獲得的固體約1〇分鐘。X射線 粉末繞射的分析顯示產物爲晶形C，如第3圖所示。 實施例5 :形式D的製備 使6 0毫克匹伐他汀鈣形式A懸浮於1毫升無水乙醇中及 在室溫攪拌2〇小時。過濾所得到的懸浮液，及在空氣中乾 燥。藉由X射線粉末繞射圖案來鑑定所得到的晶形D，如 第4圖所示。 實施例6:形式E的製備 使6 0毫克匹伐他汀鈣形式A懸浮於1，4-二噁烷和水的 混合物（1 : 1)中’及在室溫拌1 8小時。將所得到的懸浮液 過濾’及在空氣中乾燥。藉由X射線粉末繞射圖案來鑑 -21 - 201213311 定所得到的晶形E，如第5圖所示。 實施例7 :形式F的製備 使60毫克匹伐他汀鈣形式A懸浮於含20%水的3毫升甲 醇中，及在4 0 °C攪拌1小時。將所得到的懸浮液徐徐冷卻 到室溫，及繼續攪拌4小時。再度將懸浮液加熱到40°C， 攪拌30分鐘，徐徐冷卻到室溫，及攪拌另1 5小時。將懸浮 液過濾，及在空氣中乾燥所獲得的白色固體。藉由X射線 粉末繞射圖案來鑑定所得到的晶形F，如第6圖所示。 實施例8 :非晶形的製備 使62毫克匹伐他汀鈣形式A懸浮於0.3毫升1,4-二噁烷 中。於此攪拌過的溶液中，於室溫徐徐加入2.3毫升正庚 烷，及攪拌另1 6小時。將所得到的懸浮液過濾，及在空氣 中乾燥。所得到的固體經第7圖（上部）中的X射線粉末繞射 圖案證實係爲非晶形。 實施例9 :非晶形的製備 使60毫克匹伐他汀鈣形式A懸浮於1.5毫升乙基甲基酮 中。於此溶液內，每30秒添加1毫升，而總共添加21毫升 的甲基第三丁基醚，於室溫攪拌所得到的懸浮液約1 6小時 。將所得到的懸浮液過濾，及在空氣中乾燥所得到的固體 。產物的X射線繞射硏究顯示其爲非晶形，見第7圖（下部） 。藉由熱重量分析法聯合FT-IR光譜法來更進一步鑑定所 -22- 201213311 獲得的產物’透露樣品含有約5.5 %的甲基第三丁基醚。微 差掃描量熱法顯示樣品具有約68艽的玻璃轉移溫度。 【圖式簡單說明】 第1圖係形式A的特徵X射線粉末繞射圖案。 第2圖係形式B的特徵X射線粉末繞射圖案。 第3圖係形式C的兩個特徵X射線粉末繞射圖案。 第4圖係形式D的特徵X射線粉末繞射圖案。 第5圖係形式E的特徵X射線粉末繞射圖案。 第6圖係形式F的特徵X射線粉末繞射圖案。 第7圖係非晶形的兩個特徵X射線粉末繞射圖案。 -23-Interval [Α] Angle [2Θ] Relative Strength 20.0 4.4 VW 17.7 5.0 S 13.4 6.6 S 13.1 6.8 S 10.0 8.9 S 8.8 10.0 m 8.6 10.3 S 8.2 10.8 m 6.6 13.3 s 6.5 13.6 τη 6.3 14.0 s 5.84 15.2 VW 5.56 15.9 w 5.39 16.4 w 5.24 16.9 VW 4.99 17.8 VW 4.84 18.3 m 4.69 18.9 w 4.39 20.2 vs 4.34 20.4 m 4.30 20.7 m 4.24 20.9 m 4.21 21.1 vs 4.12 21.6 m 4.08 21.7 m 3.99 22.3 m 3.77 23.5 m 3.73 23.8 m 3.69 24.1 w 3.60 24.7 VW 3.50 25.4 VW 3.35 26.6 m 2.96 30.2 w 2.64 34.0 VW -12- 201213311 The present invention is a system of (3^?, 5 5)-7-[2-cyclopropyl-4-(4-fluorophenyl) quinine a crystalline polymorph of phenyl-3-yl]-3,5-dihydroxy-6-(penta)-heptanoic acid hemi-calcium salt, referred to herein as Form F, which exhibits a characteristic X-ray powder diffraction pattern with The characteristic peaks represented by d-値(A) and 2Θ in Table 6. -13- 201213311 6 = d-spacing and 2Θ angular spacing of form F [A] Angle [2Θ] Relative strength 17.2 5.1 m 15.8 5.6 W 12.6 7.0 S 10.0 8.8 m 9.2 9.6 s 8.7 10.2 w 8.1 10.9 m 7.8 11.3 w 7.4 11.9 m 7.1 12.5 m 6.8 13.0 s 6.5 13.7 m 6.2 14.4 s 6.04 14.7 m 5.79 15.3 vw 5.70 15.5 w 5.28 16.8 m 5.03 17.6 w 4.85 18.3 m 4.61 19.3 m 4.51 19.7 m 4.30 20.6 m 4.18 21.2 vs 4.08 21.8 s 3.90 22.8 s 3.84 23.1 w 3.74 23.8 W, shoulder 3.69 24.1 s 3.59 24.8 s 3.46 25.7 m 3.40 26.2 vw 3.35 26.6 m 3.31 26.9 w 3.14 28.4 w 3.02 29.5 w 3.00 29.8 vw 2.89 30.9 m -14- 201213311 Small changes in the experimental details may result in Another deviation of d-値(A) and 2Θ of the characteristic peaks in the diffraction pattern of the X-ray powder powder is another object of the present invention (3Λ,5·5)-7-[2-cyclopropyl-4-(4- Amorphous form of fluorophenyl) sialolin-3-yl]-3,5-dihydroxy-6-(£:)-heptanoic acid hemi-calcium salt, which exhibits the characteristic X-ray powder diffraction shown in FIG. pattern. Powder X-ray diffraction was performed on a Philips 1710 powder diffractometer using Cu k(a 1) radiation (1.54060A); 2 angles were recorded with an experimental error of ±0.1-0.2°. A discussion of X-ray powder diffraction patterns can be found in the "X-ray diffraction program" by J. Wiley, New York, Η. P. Klug and L. E. Alexander. Further, the present invention is directed to a method for preparing forms A, B, C, D, E and F of pitavastatin and an amorphous form. Generally, it can be prepared from the reaction of pitavastatin sodium with hydrazine & (: 丨 2 in an aqueous reaction medium) or, in the field, by free acid ((3i?, 5S)-7-[2-cyclopropyl -4-(4-Fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-(E)-heptanoic acid) or the corresponding internal vinegar is reacted with Ca(〇H)2 to obtain the present Form a of the invention. The aqueous reaction medium usually contains at least 80% by weight of water; preferably water or a water containing a small amount of solvent and/or reactants from the previous step. Form A may contain up to 15% water, Preferably, it is from about 3 to 12 ° / Torr, more preferably from 9 to 11 % water. Form B can generally be prepared by suspending Form A in ethanol as a cosolvent with water. Form C can usually be obtained by Form a is suspended in isopropanol containing water as a cosolvent. The amount of water is preferably from about 1 to 50%, especially from 1 to 20%, and more preferably about 5%. Form C may also be from isopropanol. A mixture with a ketone solvent is used to prepare -15 to 201213311. Preferably, the ketone solvent is acetone, and the amount of the ketone solvent is from about 1 to 30%, more preferably about 10%. The amount of water is preferably from about 1 to 2. 0%, preferably about 5%. Form D can usually be suspended by Form A The oxime form E obtained in anhydrous ethanol can usually be obtained by suspending the form A in 1,4-dioxane which is a co-solvent as a co-solvent. The amount of water is preferably from about 1 to 50%. Generally, the amount of β water can be preferably from about 1 to 50% by suspending Form A in methanol containing water as a cosolvent. In the above method, a small amount of crystal form of the desired crystal form can be added to the reaction mixture. Preferably, the amount is from about 1 to 20% by weight, preferably about 5% by weight. The seed crystal may be added before or after the step of crystallization (for example, cooling, addition of a non-solvent, etc., as described above). The addition before the start of crystallization is technically particularly interesting. A non-solvent can usually be added to a concentrated solution of pitavastatin calcium in an organic solvent to prepare an amorphous form. The non-solvent can be, for example, heptane or methyl. a third butyl ether, and examples of the organic solvent are 1,4-dioxane, tetrahydrofuran and ethyl methyl ketone. Preferably, the non-solvent and the solvent are immiscible. It can also be obtained by the aqueous solution of pitavastatin Freeze-drying to prepare amorphous" polymorphs A, Β, C, D, Ε, F The preparation of the amorphous form is usually carried out in a substantially pure reaction system consisting essentially of a specific educt (preferably a substantially crystalline form) and the above-mentioned solvent and/or non-solvent. Another object of the present invention is the essence. A method for preparing a crystal form of pitavastatin calcium without a residual organic solvent. In particular, the present invention relates to a method for preparing a crystal form of pitavastatin-16-201213311 without residual organic solvent, which is obtained by The crystalline form of statin calcium is exposed to the atmosphere having a defined relative air humidity. More particularly, the present invention is directed to a process for the preparation of any crystalline or amorphous form of pitavastatin calcium which is substantially free of residual organic solvents. These can be obtained, for example, by exposing the crystalline or amorphous form to an atmosphere having a relative air humidity of 5 to 1%. Preferably, these are made by exposure to an inert gas stream having a defined relative air humidity to allow the water to exchange residual organic solvent. Usually, a relative air humidity of 5 to 100% is used, especially 4 to 80%. Another object of the invention is a pharmaceutical composition comprising an effective amount of crystalline polymorph A, B, C, D, E or F or an amorphous form of pitavastatin calcium, and a pharmaceutically acceptable carrier. These polymorphs can be used as a single component or as a mixture with other crystalline or amorphous forms. With respect to the novel polymorphism and amorphous form of pitavastatin calcium, it is preferred that these contain from 25% to 10.0% by weight of at least one of the novel forms, especially 5〇_1〇〇% by weight, which is pitavastatin calcium. The total amount is based on the benchmark. Preferably, the amount of novel polymorph or amorphous form of pitavastatin calcium is from 7 5 to 10% by weight, especially from 90 to 100% by weight. The height is preferably 95-100% by weight. The compositions of the present invention comprise at least one novel form of powder, granules, condensate and other solid compositions. Further, the composition contemplated by the present invention may further comprise a diluent such as a material derived from cellulose such as powdered cellulose, microcrystalline cellulose, fine cellulose, methyl cellulose, ethyl cellulose, and B. Cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, -17-201213311 carboxymethyl, cellulose salt and other substituted and unsubstituted cellulose; starch; pregelatinized starch: inorganic thinner Such as calcium carbonate and calcium diphosphate and other diluents known to the pharmaceutical industry. Other suitable diluents include waxes, sugars and sugar alcohols such as mannitol and sorbitol, acrylic acid vinegar polymers and copolymers, as well as pectins, dextrin and gelatin. Other excipients within the scope of the present invention include binders such as acacia, pregelatinized starch, sodium alginate, glucosamine, and other binders used in wet and dry granulation or direct compression processes. Excipients which may be present in the solid composition include disintegrating agents such as sodium starch glycolate, polyvinylpolypyrrolidone, low substituted hydroxypropylcellulose, and the like. In addition, the excipient may also contain tableting lubricants such as magnesium and calcium stearate and sodium stearyl fumarate; flavoring agents: sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as Yttrium oxide. Dosages include those suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalation, and ophthalmic administration. While the most suitable route in a particular case depends on the nature and severity of the condition being treated, the best route of the invention is oral. Dosages are conveniently presented in unit dosage form and can be prepared by any methods known in the pharmaceutical art. Dosage forms include solid dosage forms such as tablets, powders, capsules, suppositories, sachets, lozenges and lozenges, as well as liquid suspensions and elixirs. The description is not intended to be limiting, and the invention is also not intended to be a true solution of pitavastatin calcium and lose the solid form of pitavastatin calcium. However, the preparation of the solution in a novel form is considered to be within the scope of the present invention. -18-201213311 Of course, the capsule will contain a solid composition within the capsule which may be made from gelatin or other conventional encapsulating material. Tablets and powders can be coated. Tablets and powders can be covered by casings. The enteric coated powder may have a coating layer comprising phthalic acid and cellulose acetate, hydroxypropylmethyl-cellulose phthalic acid vinegar, polyvinyl phthalate, carboxymethyl ethyl cellulose , a copolymer of styrene and maleic acid, a copolymer of methacrylic acid and methyl methacrylate, and the like, and if necessary, they may also be a suitable plasticizer and/or extender. The coated tablet may have a coating layer on the surface of the tablet, or may be a tablet comprising a powder and particles having a casing. A preferred unit dose of the pharmaceutical composition of the present invention typically comprises from 0.5 to 100 mg of the novel form of pitavastatin calcium and mixtures thereof with others, or other forms of pitavastatin calcium. More typically, the combined weight of pitavastatin calcium forms a unit dose of from 2.5 mg to 80 mg, such as 5, 10, 20 or 40 mg. [Embodiment] The following examples illustrate the invention in more detail. The temperature is in degrees Celsius. Example 1: Preparation of Form A 4.15 g of (3^?,55)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5 · two Hydroxy-6-(penta)-heptanoic acid tert-butyl vinegar (pitvastatin tert-butyl ester) was suspended in a 52 ml mixture of methyl tert-butyl ether and methanol (1::3). To this mixture, 2.17 ml of a 4 M aqueous NaOH solution was added at 50. C The yellowish solution produced by -19-201213311 was stirred for 2.5 hours. The reaction mixture was cooled to room temperature, then 50 ml of water was added and stirred for another hour. The aqueous phase was separated and extracted once with 20 ml of methyl tert-butyl ether. In this aqueous solution, a solution of 0.58 g of CaCl 2 in 80 ml of water was added over 1 hour. The resulting suspension was stirred at room temperature for about 16 hours. The suspension was filtered and dried over 40 ° C and 50 mbar for about 16 hours. The product obtained was Form A, which was identified by an X-ray powder diffraction pattern as shown in Figure 1. The obtained Form A was further characterized by thermogravimetric analysis in combination with FT-IR spectroscopy, revealing a water content of about 10%, while differential scanning calorimetry revealed a melting point of 95 °C. Example 2: Preparation of Form B 100 mg of pitavastatin calcium form A was suspended in 2 ml of water and stirred at room temperature for 30 minutes' followed by the addition of 2 ml of ethanol and stirring for another 18 hours. The suspension was filtered and dried in air to yield 36 mg of Form B. The resulting crystalline form B was identified by X-ray powder diffraction pattern as shown in Fig. 2. Form B obtained by thermogravimetric analysis combined with FT-IR spectroscopy was further developed to reveal a water content of about 10%. Example 3: Preparation of Form C 62 mg of pitavastatin calcium form A was suspended in 2 ml of isopropyl alcohol containing 5% water. The suspension was heated to 60 ° C while allowing form a to almost completely dissolve: and dissolve again to room temperature. The suspension was stirred at this temperature for 66 hours. The suspension obtained in the furnace was washed with some isopropyl alcohol containing 5% water, and then - 20-201213311 and dried in air. The resulting crystalline form C was identified by a ray-ray powder diffraction pattern as shown in Fig. 3. Further analysis of the obtained form c' revealed by thermogravimetric analysis in combination with FT-IR spectroscopy revealed that the sample contained about 6.3 % isopropanol and a small amount of water. Example 4: Preparation of Form C 65 mg of pitavastatin calcium form A was suspended in a mixture of 0.9 ml of isopropanol, 0.1 ml of acetone and 40 microliters of water. The suspension was stirred for about 1 hour to allow it to dissolve almost completely. Seeding was carried out with 4 mg of Form C (from Example 3) and stirred for 2 hours to form a concentrated suspension. The suspension was diluted with an equal amount of the solvent mixture as described above and stirred for another 40 hours. The suspension was filtered, and the obtained solid was dried at 40 ° C for about 1 minute. Analysis of the X-ray powder diffraction showed the product to be crystalline Form C as shown in Figure 3. Example 5: Preparation of Form D 60 mg of pitavastatin calcium form A was suspended in 1 ml of absolute ethanol and stirred at room temperature for 2 hours. The resulting suspension was filtered and dried in air. The resulting crystal form D was identified by an X-ray powder diffraction pattern as shown in Fig. 4. Example 6: Preparation of Form E 60 mg of pitavastatin calcium form A was suspended in a mixture of 1,4-dioxane and water (1:1) and mixed at room temperature for 18 hours. The resulting suspension was filtered' and dried in air. The crystal form E obtained by the X-ray powder diffraction pattern is as shown in Fig. 5. Example 7: Preparation of Form F 60 mg of pitavastatin calcium form A was suspended in 3 ml of methanol containing 20% water and stirred at 40 ° C for 1 hour. The resulting suspension was slowly cooled to room temperature and stirring was continued for 4 hours. The suspension was again heated to 40 ° C, stirred for 30 minutes, slowly cooled to room temperature, and stirred for another 15 hours. The suspension was filtered and the obtained white solid was dried in air. The resulting crystalline form F was identified by an X-ray powder diffraction pattern as shown in Fig. 6. Example 8: Preparation of amorphous form 62 mg of pitavastatin calcium form A was suspended in 0.3 ml of 1,4-dioxane. To the stirred solution, 2.3 ml of n-heptane was slowly added at room temperature, and stirred for another 16 hours. The resulting suspension was filtered and dried in air. The obtained solid was confirmed to be amorphous by the X-ray powder diffraction pattern in Fig. 7 (upper part). Example 9: Preparation of amorphous form 60 mg of pitavastatin calcium form A was suspended in 1.5 ml of ethyl methyl ketone. To this solution, 1 ml was added every 30 seconds, and a total of 21 ml of methyl tert-butyl ether was added, and the resulting suspension was stirred at room temperature for about 16 hours. The resulting suspension was filtered and the resulting solid was dried in air. The X-ray diffraction of the product showed an amorphous shape, see Figure 7 (bottom). Further analysis of the product obtained by -22-201213311 by thermogravimetric analysis combined with FT-IR spectroscopy revealed that the sample contained about 5.5% of methyl tert-butyl ether. Differential scanning calorimetry showed the sample to have a glass transition temperature of about 68 Å. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a characteristic X-ray powder diffraction pattern of Form A. Figure 2 is a characteristic X-ray powder diffraction pattern of Form B. Figure 3 is a diagram of two characteristic X-ray powder diffraction patterns of Form C. Figure 4 is a characteristic X-ray powder diffraction pattern of Form D. Figure 5 is a characteristic X-ray powder diffraction pattern of Form E. Figure 6 is a characteristic X-ray powder diffraction pattern of Form F. Figure 7 is an amorphous two-beam X-ray powder diffraction pattern. -twenty three-

Claims (1)

201213311 七、申請專利範圍： 1. 一種（3Λ，5·5)-7-[2-環丙基-4-與（4-氟苯基）喹啉-3-基 ]-3,5 -二羥基-6-(丑）-庚酸半鈣鹽之結晶多晶形Β，其表現— 種特徵X射線粉末繞射圖案，具有在2Θ表示的特徵峰，於 4.6(w) 、 5.3(vs) 、 6.2(s) 、 7.7(s) 、 9.2(m) 、 9.6(m)、 10.3(w)、11.3(m)、11.7(w)、12.6(vw)、13.0(w)、13.9(m) 、14.7(vw)、14.9(w)、15.6(w)、16.3(m)、17.0(vw)、 17.4(vw)、18.0(w)、18.7(m)、19.3(m)、20.0(s)、20.5(w) 、20·8(χη)、21.2(w,肩部）、21.5(m)、22.4(m)、23.2(s)、 23.8(m)、24.4(vw)、25.2(w、寬）、26.0(w)、26.4(vw)、 27.0(w)、27.9(vw)、28.9(w)’其中（vs)代表非常強的強度 ’（s)代表強的強度，（m)代表中等強度’（w)代表弱的強度 ’（vw)代表非常弱的強度。 2. —種（3A，5S)-7-[2-環丙基-4-(4-氟苯基）喹啉-3-基]-3,5-二羥基_6_(五）_庚酸半鈣鹽的結晶多晶形b，其具有實 質上如以下所示的X射線粉末繞射圖案：201213311 VII. Patent application scope: 1. One (3Λ,5·5)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-two a polycrystalline form of hydroxy-6-(ugly)-heptanoic acid hemi-calcium salt, characterized by a characteristic X-ray powder diffraction pattern having a characteristic peak at 2 ,, at 4.6 (w), 5.3 (vs), 6.2(s), 7.7(s), 9.2(m), 9.6(m), 10.3(w), 11.3(m), 11.7(w), 12.6(vw), 13.0(w), 13.9(m), 14.7 (vw), 14.9 (w), 15.6 (w), 16.3 (m), 17.0 (vw), 17.4 (vw), 18.0 (w), 18.7 (m), 19.3 (m), 20.0 (s), 20.5(w), 20·8(χη), 21.2(w, shoulder), 21.5(m), 22.4(m), 23.2(s), 23.8(m), 24.4(vw), 25.2(w, width ), 26.0 (w), 26.4 (vw), 27.0 (w), 27.9 (vw), 28.9 (w) 'where (vs) represents a very strong intensity '(s) represents a strong intensity, and (m) represents a medium The strength '(w) represents a weak intensity '(vw) represents a very weak intensity. 2. (3A,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6-(5)-heptanoic acid A crystalline polymorph b of a semi-calcium salt having an X-ray powder diffraction pattern substantially as shown below: 3.—種（3/?，5*5)-7-[2-環丙基-4-(4-氟苯基）喹啉-3-基]- -24- 201213311 3，5-二羥基-6-(五）-庚酸半鈣鹽之結晶多晶形F，其表現一種 特徵X射線粉末繞射圖案，具有在2Θ表示的特徵峰，於 5.1(m)、5.6(w)、7.0(s)、8.8(m)、9.6(s)、l〇.2(w)、 10.9(m)、11.3(w)、11.9(m)、12.5(m)、13.0(s)、13.7(m) 、14.4(s)、14.7(m)、15.3(vw)、15.5(w)、I6.8(m)、 17.6(w)、18.3(m)、19.3(m)、19.7(m)、20.6(m)、21.2(vs) 、21.8(s)、22.8(s)、23.1(w)、23.8(w，肩部）、24.1(s)、 24.8 (s) ' 25.7(m)、26.2(vw)、26.6(m)、26.9(w)、2 8.4 (w) 、29.5(w)、29.8(vw)、30.9(m)，其中（vs)代表非常強的強 度，（s)代表強的強度，（m)代表中等強度，（w)代表弱的強 度，（vw)代表非常弱的強度。 4.—種（3/?，5<S)-7-[2-環丙基-4-(4-氟苯基）喹啉-3-基]-3,1-二羥基-6-(五）-庚酸半鈣鹽之結晶多晶形F，其具有實質 上如下所示的X射線粉末繞射圖案： 200 1000 1200 000000 8 6 4 截41¾缌3.-(3/?,5*5)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]- -24- 201213311 3,5-dihydroxy Crystalline polymorph F of -6-(f)-heptanoic acid hemi-calcium salt, which exhibits a characteristic X-ray powder diffraction pattern with characteristic peaks at 2 ,, at 5.1 (m), 5.6 (w), 7.0 ( s), 8.8(m), 9.6(s), l〇.2(w), 10.9(m), 11.3(w), 11.9(m), 12.5(m), 13.0(s), 13.7(m) , 14.4 (s), 14.7 (m), 15.3 (vw), 15.5 (w), I6.8 (m), 17.6 (w), 18.3 (m), 19.3 (m), 19.7 (m), 20.6 ( m), 21.2 (vs), 21.8 (s), 22.8 (s), 23.1 (w), 23.8 (w, shoulder), 24.1 (s), 24.8 (s) ' 25.7 (m), 26.2 (vw) , 26.6 (m), 26.9 (w), 2 8.4 (w), 29.5 (w), 29.8 (vw), 30.9 (m), where (vs) represents a very strong intensity and (s) represents a strong intensity, (m) represents moderate strength, (w) represents weak strength, and (vw) represents very weak intensity. 4.-(3/?,5<S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,1-dihydroxy-6-( 5) a crystalline polymorph F of a heptanoic acid hemi-calcium salt having an X-ray powder diffraction pattern substantially as follows: 200 1000 1200 000000 8 6 4 Section 413⁄4缌 15 20 2Θ角 25 30 3S15 20 2 corner 25 30 3S -25- 1 —種製備如申請專利範圍第1或2項之結晶多晶形B 之方法，其包括使結晶多晶形A懸浮於含水當作共溶劑的 201213311 中 醇 乙 基 丙 甲[2-半 $α7 酸 $}-庚 6 S . 5 \—/， 五 J 圍 範 利 專 請 4 /IV 基 :苯 第氟 法 方 之 項 至 11 的 液 浮 懸 之 鹽 鈣 基 - 0 -3% 啉積 喹體 爲基 係羥 量二 水5-中-3, 其1 形 晶 多 晶 結 之 項 4 或 3 第 圍 範 利 專 請 甲 如 備 製 amp 種 之方法’其包括使如申請專利範圍結晶多晶形A懸浮於含 水當作共溶劑的甲醇中。 8·如申請專利範圍第7項之方法，其中水量係爲 (3及，5*5)-7-[2-環丙基-4-(4-氟苯基）喹啉-3-基]-3,5-二羥基-6-(五）-庚酸半鈣鹽之懸浮液的1至50體積％。 9.~種製備本質上無殘留有機溶劑的（3及，5^)-7-[2-環 丙基-4-(4-氟苯基）喹啉-3-基]-3,5-二羥基-6-(五）-庚酸半鈣 鹽的結晶多晶形B或F之方法，其係藉由使此晶形暴露於具 有相對空氣濕度爲5至100%的大氣中。 1G· —種製備製備本質上無殘留有機溶劑的（3i?，5S)-7-[2-環丙基_4-(4-氟苯基）唼啉-3-基]-3,5-二羥基- 6-(E)-庚酸 半#5鹽的結晶多晶形8或F之方法，其係藉由使此晶形在一 具有相對空氣濕度爲5至i 〇〇%的惰性氣流中平衡。 1 1 · 一種藥學組成物，包括有效量的如申請專利範圍 第1 Μ 4項中任一項之結晶多晶形，及藥學上可接受性載體 -26-A method for preparing a crystalline polymorph B according to claim 1 or 2, which comprises suspending crystalline polymorph A in an alcoholic ethyl propyl group [2-half] in 201213311 containing water as a cosolvent. $α7 Acid $}-Geng 6 S . 5 \—/, Five J Wei Fanli Special 4/IV Base: Benzene Fluorine Method to 11 Liquid Floating Salt Calcium Base - 0 -3% Porphyrin The quinone is a hydroxy group of dibasic 5-mer-3, and its 1-form crystal polycrystalline knot is 4 or 3, and the following method is used to prepare the amp species. The crystalline polymorph A is suspended in methanol containing water as a cosolvent. 8. The method of claim 7, wherein the amount of water is (3 and 5*5)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl] 1 to 50% by volume of a suspension of -3,5-dihydroxy-6-(penta)-heptanoic acid hemi-calcium salt. 9.~ Preparation of (3 and 5^)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5- without residual organic solvent A method of crystallizing polymorph B or F of dihydroxy-6-(penta)-heptanoic acid hemi-calcium salt by exposing the crystalline form to an atmosphere having a relative air humidity of 5 to 100%. 1G· Preparation of (3i?,5S)-7-[2-cyclopropyl-4(4-fluorophenyl)porphyrin-3-yl]-3,5- without residual organic solvent A method of crystall polymorph 8 or F of a dihydroxy-6-(E)-heptanoic acid hemi- 5 salt by balancing the crystal form in an inert gas stream having a relative air humidity of 5 to 9% . 1 1 · A pharmaceutical composition comprising an effective amount of a crystalline polymorph as set forth in any one of claims 1 to 4, and a pharmaceutically acceptable carrier -26-
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